Monday, June 30, 2025 6/30/2025

Neuroprotection by a Secreted Component of the Cellular Stress Response

Award Number: R01NS121337
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Neuroprotection by a Secreted Component of the Cellular Stress Response - PROJECT SUMMARY We found that neurons secrete a soluble protein that protects neurons under cell stress conditions in a paracrine manner. Remarkably, this protein is derived from the C-terminus of the endoplasmic reticulum (ER) membrane bound transcription factor CREB3L2. Proteolytic cleavage liberates the N-terminal transcription factor and leads to the secretion of the ER luminal domain into the extracellular space. Our preliminary data indicate that the production and secretion of this C-terminal domain is triggered by cell stress and that it acts by increasing mitochondrial function via sonic hedgehog (Shh) signaling. In this project we are testing the general hypothesis that CREB3L2-C is a paracrine component of the adaptive neuronal stress response. We will culture primary rat cortical neurons and expose them to various cell stress triggers, including oxidative stress, ER stress, proteasome inhibition, and glucose-deprivation. We will determine whether the activation of the integrated stress response pathway is necessary and sufficient to upregulate the synthesis and cleavage of CREB3L2. We will investigate how the luminal C-terminal domain of CREB3L2 is secreted from cells and whether its secretory pathway is linked to cell stress. To investigate how the secreted C-terminal domain of CREB3L2 affects neurons, we will purify it and apply it to primary cortical neurons. We will focus on its proposed role in strengthening Shh signaling and determine whether it forms complexes with Shh and its receptor Patched-1 on neurons. We will determine whether application of the secreted, C-terminal domain of CREB3L2 is sufficient to increase Shh signaling and whether enhanced Shh signaling is necessary for its effects on cell survival and mitochondrial function. To assess the effect of the secreted C-terminal domain of CREB3L2 on mitochondria, we will employ a variety of tests to quantify changes to mitochondrial mass, abundance of mitochondrial proteins, and mitochondrial function in neurons under normal conditions and upon induction of oxidative stress, ER stress, proteasome inhibition, and glucose-deprivation. The cleavage of CREB3L2 activates necessarily two distinct signaling molecules, the intracellular transcription factor and the secreted C-terminus. We will use chromatin immunoprecipitation with sequencing in combination with RNA sequencing to determine the transcriptional targets of CREB3L2 in neurons under baseline and induced stress conditions, to determine whether both signaling molecule act cooperatively in the adaptive cell stress response. Lastly, we will use a previously generated conditional CREB3L2 knockout mouse to study the relative roles of the cell autonomous (i.e. the transcription factor) and the non-cell autonomous arm of CREB3L2 signaling in neuronal stress response in vitro and in vivo. Together, the results from this project will uncover a novel intercellular signaling pathway that is activated in response to cell stress in neurons and confers enhanced resilience and mitochondrial function to receiving neurons.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $498,973 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/1/2025	NON-COMPETING CONTINUATION	$498,973
														Subtotal = $498,973

Issue Date FY: 2024 ( Subtotal = $517,362 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/27/2023	NON-COMPETING CONTINUATION	$480,026
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/10/2024	NON-COMPETING CONTINUATION	$37,336
														Subtotal = $517,362

Issue Date FY: 2023 ( Subtotal = $833,049 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/23/2022	NON-COMPETING CONTINUATION	$474,012
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/30/2023	NON-COMPETING CONTINUATION	$52,668
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	3/21/2023	SUPPLEMENT FOR EXPANSION	$306,369
														Subtotal = $833,049

Issue Date FY: 2022 ( Subtotal = $526,680 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/5/2022	NEW	$526,680
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/26/2022	NEW	$0
														Subtotal = $526,680

Grand Total All Awards = $2,376,064

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Neuroprotection by a Secreted Component of the Cellular Stress Response

Award Number: R01NS121337

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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